Nadir PSA is a strong predictor of treatment outcome in intermediate and high risk localized prostate cancer patients treated by definitive external beam radiotherapy and androgen deprivation.
ABSTRACT: The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high risk prostate cancer treated by combined definitive external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT).Between June 1995 and January 2015, 375 patients with localized prostate cancer and a National Comprehensive Cancer Network (NCCN) intermediate or high risk categories were treated by definitive EBRT and ADT. Median duration of androgen blockade was 10 months (range: 3-36 months); Median radiation dose was 72 Gy (Range: 70-78 Gy). Median follow-up time was 5.8 years (range: 0.8-16.39 years). The main study endpoint was biochemical disease free survival (BFS).Forty seven patients (12.5%) developed biochemical recurrence (BCR) during the observation period. Monovariate analysis identified baseline PSA (bPSA) (p = 0.024), T-stage (p = 0.001), Gleason's score (GS) (p = 0.042), radiation dose (p = 0.045), PSA pre-radiation therapy (p = 0.048), and nadir PSA (nPSA), (p < 0.001) as significant variables affecting BCR. The receiver operating characteristic (ROC) curve identified a nPSA of 0.06 ng/ml as optimal cut-off value significantly predicting the patients' risk of BCR (p < 0.001). Multivariate cox regression analysis revealed T-stage, GS, and nPSA as independent variable affecting BFS, while bPSA, age, and radiation dose were not.Nadir PSA at 0.06 is a strong independent predictor of BFS in patients with intermediate or high risk prostate cancer treated by definitive EBRT and ADT.
Project description:<b>Introduction: </b>High-risk prostate cancer is associated with poorer overall survival (OS) and biochemical control compared to more favorable risk groups. External beam radiation therapy (EBRT) is widely used; however, outcomes data are limited with respect to time elapsed between diagnosis and initiation of EBRT.<br><br><b>Methods: </b>The National Cancer Database was queried from 2004 to 2015 for patients diagnosed with high-risk adenocarcinoma of the prostate who received androgen deprivation therapy (ADT) and definitive EBRT. Logistic regression was utilized to determine covariates associated with missing EBRT treatments. OS was analyzed using multivariate cox proportional hazards models and propensity score matching.<br><br><b>Results: </b>9,610 patients met inclusion criteria with median follow-up of 40.6 months and median age of 72 years. Median PSA was 8.7 and median EBRT dose was 78 Gy. ADT was initiated at a median of 36 days and EBRT at a median of 63 days post-diagnosis. Median number of prolonged treatment days was 2.2. Black race (OR: 1.40; <i>p</i> < 0.01), treatment at a community clinic (OR: 1.32; p < 0.01), and living in an urban/densely populated area were associated with prolonged treatment. Time elapsed between ADT and EBRT > 74 days (HR: 1.20; <i>p</i> = 0.01) and prolonged treatment>3 days of EBRT (HR: 1.26; <i>p</i> = 0.005) were associated with an increased hazard of death. The 5-year OS was 79.6% and 82.9% for patients with prolonged treatment of 3 days or more of EBRT and those missing 3 days or less, respectively (<i>p</i> = 0.0006).<br><br><b>Conclusion: </b>In this hypothesis-generating study, prolonged treatment delays and missing three or more EBRT treatments was associated with poorer OS in patients with high-risk adenocarcinoma of the prostate.
Project description:To gain beneficial effects in the management of high-risk prostate cancer, an integrated approach that combines local therapy and androgen deprivation therapy (ADT) was used. We compared biochemical responses between primary cryosurgical ablation of the prostate (CSAP) combined with prolonged ADT and radiation combined with ADT, which is the established modality in high-risk disease. A total of 33 high-risk patients received CSAP combined with ADT for 3 months before and up to 24 months after treatment. This patient group was matched with another 33 patients who had undergone three-dimensional conformal radiation therapy (3D-CRT) with the same protocol for ADT. Biochemical recurrence (BCR) was assessed by the American Society for Therapeutic Radiation Oncology (ASTRO) definition, the Phoenix definition and a prostate-specific antigen (PSA) cutoff of 0.5 ng mL(-1). Median follow-up was 61.0 ± 11.9 months for the CSAP + ADT group and 86.0 ± 15.8 months for the 3D-CRT + ADT group. In the CSAP group, major complications including rectourethral fistula and incontinence were not noted. In the CSAP + ADT group, 57.0% had BCR using the ASTRO definition, 21.2% using the Phoenix definition and 54.5% using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, 54.5%, 21.2% and 54.5% had BCR using the ASTRO, Phoenix and PSA definition, respectively. In the CSAP + ADT group, the BCR-free survival (BRFS) was 54 ± 10 months using the ASTRO definition, 65 ± 5 months using the Phoenix definition and 51 ± 4 months using a PSA cutoff of 0.5 ng mL(-1). In the 3D-CRT + ADT group, the BRFS was 68 ± 12, 93 ± 19 and 70 ± 18 months using the ASTRO, Phoenix and PSA definition, respectively. By the log-rank test, the BRFS values for each group were not statistically different. This intermediate-term result indicated that primary CSAP combined with prolonged ADT offers a parallel biochemical response compared with radiotherapy in high-risk prostate cancer.
Project description:Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT).During 1991-2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (<50?ng/dl) with progressive biochemical or radiographic disease.For the entire cohort (n?=?2,478), the 10-year cumulative incidence rate for developing CRPC was 9.9%. For those that progressed to salvage ADT (n?=?362), the 7-year cumulative incidence rates for developing CRPC from time of salvage ADT was 33.7%. Amongst this cohort, multivariable analysis demonstrated that PSA doubling-time (continuous; hazard ratio [HR], 0.98 [0.97-0.99], P?<?0.001), higher Gleason score (HR, 1.96 [1.12-3.43]; P?=?0.034), and duration of ADT at time of EBRT (continuous; HR, 1.02 [1.01-1.03]; P?=?0.007) were associated with development of CRPC.This represents the first report of predictors of CRPC for patients treated with modern dose-escalated EBRT. We demonstrate that among the minority of patients not initially cured after EBRT, those treated with longer-course ADT have higher rates of resistance to the re-introduction of ADT. Future trials will need to test this subgroup with more aggressive or alternative forms of salvage therapies.
Project description:<h4>Background</h4>The addition of androgen-deprivation therapy (ADT) or pelvic radiation to prostate bed salvage radiotherapy (SRT) has been debated for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy. This study aimed to assess the outcomes and propose prediction models for exclusive prostate bed SRT.<h4>Methods</h4>This is a prospective observational cohort study with patients who underwent SRT with a pre-SRT PSA < 1.5 ng/mL after radical prostatectomy. Patients were treated with 70-Gy SRT to the prostate bed exclusively. Kaplan-Meier survival analyses and Cox regression analyses were applied for depicting and predicting BCR-free survival, ADT-free survival, and metastasis-free survival (MFS). Regression-based coefficients were used to develop nomograms.<h4>Results</h4>A total of 105 patients were included and 91 patients were eligible. The median follow-up period was 39 months. The 5-year BCR-free survival, ADT-free survival, and MFS were 37%, 50%, and 66%, respectively. Multivariable analysis showed that a pre-SRT PSA < 0.45 ng/mL was the only independent factor associated with longer BCR-free survival (<i>p</i> = 0.034), while a PSA-DT > 8 months had better ADT-free survival (<i>p</i> = 0.008). Patients with a PSA-DT > 8 months showed a 100% MFS and a 43% 5-year absolute benefit in MFS than a PSA-DT ≤ 8 months. All patients with a pre-SRT PSA < 0.45 ng/mL and PSA-DT > 8 months were free from subsequent ADT and any metastasis.<h4>Conclusions</h4>In patients with a PSA < 0.45 ng/mL and PSA-DT > 8 months for post-prostatectomy BCR, prostate bed SRT provided excellent outcomes without the need for concomitant ADT or pelvic radiotherapy.
Project description:<h4>Background</h4> Intermediate-risk prostate cancer (PCa) is usually treated by a combination of external beam radiation therapy (EBRT) and a short course of androgen deprivation therapy (ADT). ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, anti-androgen monotherapy is generally better tolerated in spite of higher rates of gynecomastia. <h4>Objective</h4> This study assessed the effectiveness of enzalutamide monotherapy combined with hypofractionated EBRT (Hypo-EBRT) for treating intermediate risk prostate cancer. <h4>Method</h4> This trial was a multicenter, open-label phase II study of 6 months of enzalutamide monotherapy combined with Hypo-EBRT for intermediate-risk prostate cancer. Hypo-EBRT was initiated 8–12 weeks after initiating enzalutamide. The primary endpoint was PSA decline >80% measured at the 25th week of enzalutamide administration. Secondary end-points included assessment of toxicity, changes in anthropomorphic body measurements, sexual hormones, and metabolic changes. <h4>Results</h4> Sixty-two patients were included in the study from January 2018 to February 2020. A PSA decline of >80% was observed in all evaluable patients at the end of enzalutamide treatment and 92% achieved PSA values under 0.1 ngr/ml. All patients remain in PSA response (<80% reduction of the initial values) 6 months after the end of enzalutamide treatment. The most frequent adverse events were hypertension, asthenia, and gynecomastia. There were no significant changes in bone density, body mass index (BMI), or patient-reported outcomes (PROs). <h4>Conclusion</h4> Enzalutamide monotherapy is very effective along with hEBRT in reducing PSA levels for patients with intermediate-risk prostate cancer. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials.
Project description:<h4>Background and purpose</h4>The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens.<h4>Materials and methods</h4>In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ?0.2 and ?0.5 ng/mL, and BCR-free survival (BCRFS).<h4>Results</h4>Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ?0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (?93% for all regimens, p ? 0.21).<h4>Conclusion</h4>Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.
Project description:<b>Purpose: </b>The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial reported overall survival benefits for prostate-directed radiation therapy (PDRT) in low-burden metastatic prostate cancer. Oligometastasis-directed radiation therapy (ORT) improves androgen deprivation therapy (ADT)-free and progression-free survivals. Comprehensive PDRT + ORT to all detectable metastases may offer benefit for de novo oligometastatic prostate cancer (DNOPC) and is under prospective study; given few available benchmarks, we reviewed our institutional experience.<br><br><b>Methods and materials: </b>Forty-seven patients with DNOPC with predominantly M1b disease received neoadjuvant, concurrent, and adjuvant ADT plus PDRT + ORT to 1 to 6 oligometastases. Gross pelvic (N1) nodes were not considered oligometastases unless focally targeted without broader nodal coverage. Outcomes were analyzed from radiation therapy (RT) start using Kaplan-Meier, competing risks, and Cox regression. Median follow-up was 27 (95% confidence interval, 16-42) months.<br><br><b>Results: </b>At 1- and 2-years post-RT, cumulative incidence of distant metastatic progression (DMP) was 21% and 32%, whereas overall survival was 90% and 87%, respectively. Neuroendocrine/intraductal histology, prostate-specific antigen (PSA) < 20, and detectable PSA after PDRT + ORT were associated with increased DMP risk; number and location of oligometastases were not. Local failure was rare, with 3 prostate recurrences and progression of 10 treated oligometastases during follow-up. After neoadjuvant ADT, 9 (19%) patients had undetectable PSA (<0.05 ng/mL), which increased to 32 (68%) after PDRT + ORT. Overall 2-year incidence of biochemical recurrence (BCR) and development of castrate resistance were 23% and 36%, respectively. Undetectable PSA post-RT was associated with lower risk of BCR (hazard ratio, 0.19; <i>P</i> = .004) and DMP (hazard ratio, 0.26; <i>P</i> = .025). Overall, 23 (49%) patients were trialed off ADT; 16 (70%) had testosterone recovery (>150 ng/dL) and, of these, 5 had subsequent PSA rise and restarted ADT 2 to 21 months postrecovery. The remaining 11 were maintained off ADT without BCR. Median noncastrate duration was 8 months; 7 patients had normalized testosterone for >1 year.<br><br><b>Conclusions: </b>A comprehensive, radiotherapeutic-based treatment strategy has favorable clinical outcomes and can produce prolonged noncastrate remissions in a subset with DNOPC.
Project description:In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification.Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ?0.1?ng?ml-1) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA.At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, P<0.001), 10-year MFS (84.8% versus 92.0%, P=0.003), 10-year PCSS (94.3% versus 98.2%, P=0.007) and 10-year OS (75.8% versus 82.5%, P=0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37-14.65, P<0.001; NCCN risk level: HR 2.01, 95% CI 0.74-5.42, P=0.168). Main study limitations are retrospective study design and associated biases.EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.
Project description:BACKGROUND AND PURPOSE:To identify early biochemical predictors of survival in intermediate- and high-risk prostate cancer patients with a pre-treatment PSA <20?ng/mL following definitive radiation therapy (RT) and androgen deprivation therapy (ADT). MATERIALS AND METHODS:A single-institution review of 2566 intermediate and high-risk prostate cancer patients treated with definitive RT and neoadjuvant and concurrent ADT from 1990 to 2012 was performed. The first prostate-specific antigen (PSA) value within three months of ADT initiation (post-ADT PSA) and the first PSA within three months after RT completion (post-RT PSA) were recorded. 1275 had baseline PSA <20?ng/mL and either post-ADT or post-RT PSA available. Median follow-up was 7.6?years. The relationship between post-treatment PSA kinetics and biochemical relapse (BR), distant metastasis (DM), prostate cancer specific death (PCSD) and overall survival (OS) was modeled using Cox regression univariate and multivariate analysis (MVA). RESULTS:MVA demonstrated a strong association between a post-RT PSA ?0.09?ng/mL and a significantly higher risk of BR (HR: 1.93; 95% CI: 1.45-2.57; p?<?0.001), DM (HR: 2.97; 95% CI: 2.01-4.39; p?<?0.001), PCSD (HR: 2.99; 95% CI: 1.73-5.15; p?<?0.001) and OS (HR: 1.49; 95% CI: 1.18-1.86; p?<?0.001). Post-RT PSA reduction of ?95% relative to the baseline PSA was associated with a significantly lower risk of BR (MVA HR: 0.58; 95% CI: 0.41-0.83; p?=?0.003) and DM (MVA HR: 0.47; 95% CI: 0.30-0.76; p?=?0.002). CONCLUSION:A PSA value ?0.09?ng/mL early after RT completion is associated with significantly worse prognosis across all clinical outcomes, and an early PSA reduction of ?95% is associated with reduced risk of BR and DM. These findings may identify patients who require early aggressive systemic management for high-risk disease.
Project description:INTRODUCTION:Brachytherapy is a well-established treatment of localized prostate cancer. Few studies have documented long-term results, specifically biochemical progression-free survival (bPFS) in men with brachytherapy alone, with or without short-term androgen deprivation therapy (ADT), or in combination with external beam radiotherapy (EBRT). Our aim was to analyze long-term bPFS of brachytherapy treated patients. MATERIALS AND METHODS:Retrospective analysis of 1457 patients with low and intermediate risk prostate cancer treated with brachytherapy alone (1255) or combined with EBRT (202). Six-months ADT was administrated for all EBRT combined patients and for prostate volume downsizing when >55 cc (328). Failure was by the Phoenix definition. Kaplan-Meier analysis and multivariate Cox regression estimated and compared 10-yr and 15-yr rates of bPFS. RESULTS:Median follow-up was 6.1 yr. Ten and 15-yr bPFS rates of the entire cohort were 93.2% and 89.2%, respectively. On multivariate analysis, PSA density (PSAD), ADT and clinical stage were significantly associated with failure. The most powerful independent factor was PSAD with a HR of 3.5 (95% CI, 1.7-7.4) for PSAD above 0.15. No significant difference was found between low and intermediate risks patients regardless of treatment regimen. However, comparison of two intermediate risk groups, Gleason score (GS) 7, PSA<20 ng/ml versus GS≤6 and PSA = 10-20 ng/ml, revealed 10- and 15-yr bPFS rates of 94.2% and 94.2% compared to 88.2% and 79.9%, (P = 0.022), respectively. ADT improved bPFS rates in low risk patients. The ten and 15-yr bPFS rates were 97.6% and 94.6% compared to 92.3% and 88.2%, (P = 0.020), respectively. CONCLUSIONS:Our retrospective large scale study suggests that brachytherapy provides excellent long-term bPFS rates in low and intermediate risk disease. Combination of brachytherapy with EBRT yields favorable outcomes in GS 7 intermediate risk patients and short-term ADT has a positive effect on outcomes in low risk patients. Further prospective studies are warranted to discriminate the role of adding either EBRT and/or ADT to brachytherapy protocols.